Download Nontuberculous (Environmental) Mycobacterial Disease

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Nontuberculous (Environmental)
Mycobacterial Disease
Nontuberculous mycobacteria (NTM) are in the same family as the organisms
that cause tuberculosis and leprosy, but unlike those organisms, NTM are widely
dispersed in our environment, vary greatly in their ability to cause disease, and
are not spread from person to person. There are about 140 different species of
mycobacteria. Mycobacteria not closely related to tuberculosis or leprosy are
called nontuberculous mycobacteria, environmental mycobacteria, and mycobacteria other than tuberculosis (MOTT). Recent studies have documented
increases in NTM infections, and, in many areas of the United States, these
infections outnumber tuberculosis.
Whom does it affect?
Epidemiology, prevalence, economic burden, vulnerable populations
Nontuberculous mycobacteria were first identified in the late 19th century, when a
tuberculosis-like disease was reported in chickens. In the 1930s, they were documented to cause disease in humans, but it was not until the 1950s that pulmonary
disease due to these organisms became more commonly recognized. Most clinicians discounted the clinical significance of these bacteria, until the acquired
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Nontuberculous mycobacterial (NTM) infections and tuberculosis (TB) case rates in
Ontario, 1997–2003
18
Cases per 100,000 population
16
14
12
10
8
6
4
2
0
1997
1998
1999
2000
2001
2002
2003
Year
MAC
Xenopi
RGM
Kansasii
All NTM
TB
Nontuberculous mycobacterial disease has increased significantly in recent years (all P < .001). These
Canadian data most likely mirror U.S. data. The rates are calculated from the total number of cases and
population data from Statistics Canada (available at: http://www.statcan.ca/english/Pgdb/demo02.htm).
MAC, Mycobacterium avium complex; RGM, rapidly growing mycobacteria; kansasii and xenopi are
species of mycobacteria. Reproduced from Isolation prevalence of pulmonary non-tuberculous
mycobacteria in Ontario, 1997–2003, Thorax, Marras TK, Chedore P, Ying AM, Jamieson F 62
661–666, 2007 with permission from BMJ Publishing Group Ltd.
immune deficiency syndrome (AIDS) epidemic, when patients with advanced
human immunodeficiency virus (HIV) disease began developing mycobacterial
infections that spread throughout their bodies. The subsequent development of
new antimicrobials demonstrated that these infections could be treated and prevented in individuals with HIV. Fortunately, the discovery of potent antiretroviral
drugs has improved the immune systems of patients with AIDS and reduced the
incidence of mycobacterial infections in these persons. However, pulmonary NTM
infections in people uninfected with HIV appear to be increasing.
Determining the number of environmental mycobacterial infections in the
United States is difficult because reporting these infections to public health
departments is not required. Survey data from state laboratories in the early
1980s estimated the prevalence of NTM infections to be 1 to 2 cases per 100,000
population (1). A similar survey from 1993–1996 reported an annual case rate of
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7 to 8 per 100,000. A recent population-based study from Ontario, Canada,
documented an increase in the frequency of environmental mycobacterial infections from 9.1 per 100,000 in 1997 to 14.1 per 100,000 in 2003, an annual
increase of 8.4 percent (2). Because these infections require therapy that generally lasts two to three times longer than that used to treat tuberculosis, and
because recurrences are more common, the prevalence of nontuberculous
mycobacterial infections in Ontario has been estimated to be 14 to 35 per
100,000, three to eight times that of tuberculosis (3).
Nontuberculous mycobacterial infections also appear to be increasing in
the United States. Studies measuring skin test reactivity found that exposure
to the most common environmental mycobacteria, Mycobacterium avium,
occurs in over 50 percent of adults in the southeastern United States, compared to about 20 percent in other regions of the country (4). The frequency of
positive skin test reactions increased from the 1970s to the 1990s, suggesting
increased exposure over that period (5). In recent skin test studies, factors
that predicted a positive reaction included being male, African American, and
born outside the United States, as well as degree of exposure to soil (5,6).
However, these factors do not necessarily indicate who will develop mycobacterial disease.
There is one published report describing the economic burden of NTM
infections (6a). This report noted that the treatment costs were comparable to
other chronic infectious diseases such as HIV/AIDS. Whereas tuberculosis is
treated with multiple drugs for six months, most NTM lung infections require
18 to 24 months of treatment. The cost of treatment per patient is probably three
or four times that of treating tuberculosis.
While anyone can develop a mycobacterial infection, most patients have
underlying structural lung disease, such as chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, prior tuberculosis, or chronic aspiration (1).
Earlier studies noted a male preponderance in patients with pulmonary disease,
but more recent reports have found a female preponderance (7,8). Among
women with pulmonary infections, there is often a constellation of physical findings: bronchiectasis, thin body habitus, curvature of the spine (scoliosis), hollowed chest (pectus excavatum), lax heart valve struts (mitral valve prolapse),
and joint hypermobility (8,9). The reason for these associations has not been
determined and, to date, no significant immunological abnormality has been
identified.
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Case Study
A 67-year-old woman saw her primary care physician for a chronic cough
that was accompanied by fatigue and weight loss. In the previous five
years, she had been treated for multiple episodes of “bronchitis” and
improved with each treatment, only to have her cough return. The patient
had been healthy most of her life with no significant medical problems, and
she never smoked. A chest radiograph showed mild lung changes near her
heart. A chest computed tomography (CT) scan demonstrated that these
abnormalities were due to bronchiectasis and that she had many small
nodules consistent with an infection. Although she was unable to produce
sputum on her own, specimens were obtained by having her inhale saline,
and these specimens eventually grew M. avium complex (MAC) in two of
three cultures after about three weeks. Because of her chronic symptoms,
abnormal radiograph, and multiple positive cultures, she was begun on a
three-drug treatment regimen with plans to treat for approximately
18 months. She improved with the treatment, and by the end of therapy,
the organism could no longer be detected in her sputum.
Comment
The lung is the most common site of NTM infections, but lymph nodes,
skin, and soft tissue in several areas of the body can also be involved.
Patients with pulmonary infections usually have chronic cough, fatigue,
malaise, and weight loss. In many instances, patients are misdiagnosed as
having chronic bronchitis and treated repeatedly with short courses of
antibiotics. Simply isolating the organisms from a respiratory specimen
does not mean that the patient has mycobacterial disease.
For years, the term colonization was used to differentiate those who had
no evidence of progressive disease from those who did. For persons
considered to be “colonized” with environmental mycobacteria, no
­treatment was prescribed. However, it is now apparent that many of the
patients who were thought to have been “colonized,” did, in fact, have
evidence of disease on CT scans and had slow progression. To help
clinicians with the difficult task of trying to determine if an NTM species is
or is not causing disease, the American Thoracic Society and Infectious
Diseases Society of America developed a set of criteria that use clinical,
radiographic, and microbiologic parameters to distinguish disease from
colonization (1).
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What are we learning about this disease?
Pathophysiology, causes: genetic, environment, microbes
The source of NTM infections appears to be environmental exposure, with no
person-to-person transmission reported. These mycobacteria are dispersed
widely in nature and have been isolated from natural and treated water as well
as soil.
Although exposure is common, disease is unusual. The importance of
host immunity in resisting infections has been demonstrated in persons with
HIV, persons taking immunosuppressive drugs, and those who have mutations of genes that produce proteins of the immune system. These patients
usually develop severe mycobacterial infections, including disseminated disease. No genetic predisposition to pulmonary disease, however, has been
discovered.
A unique clinical presentation is that of hypersensitivity pneumonitis or “hottub lung.” In this condition, exposure to environmental mycobacteria in contaminated water can result in an inflammatory response in the lung that can be quite
serious. These patients experience shortness of breath and have diffuse abnormalities on their chest radiographs.
NTM are traditionally divided into slowly and rapidly growing organisms,
although all grow much slower than most other bacteria. They display a wide
range of ability to cause disease (pathogenicity): some species do not cause
Some common slowly and rapidly growing nontuberculous mycobacteria
causing pulmonary infections
S lowly growing mycobacteria
Rapidly growing mycobacteria
M. avium
M. abscessus
M. intracellulare
M. chelonae
M. kansasii
M. fortuitum
M. malmoense
M. simiae
M. szulgai
M. xenopi
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Dean E. Schraufnagel
Through this microscope, Robert Koch was
the first to view the mycobacteria that cause
tuberculosis. He also found mycobacteria in
animals and other environments and noted
differences in their appearances that brought
forth the concept that not all mycobacteria
cause tuberculosis.
­ isease in humans, some produce disease occasionally, and others almost always
d
cause disease if they are found in sputum. The reason for this variation in pathogenicity is not known. Keeping track of the many different mycobacterial species
and which ones are likely to cause disease can be daunting for c­ linicians.
How is it prevented, treated, and managed?
Prevention, treatment, staying healthy, prognosis
An effective strategy for preventing pulmonary NTM infections is lacking. Except
in the case of “hot-tub lung,” where ceasing exposure to contaminated water can
result in resolution of the condition, it is unknown how to prevent these infections. NTM have been isolated from public water supplies and pose a sterilization problem because they tolerate high water temperature and are resistant to
standard decontamination methods.
Although antituberculous drugs have been used widely to prevent the development of tuberculosis, such therapy for NTM is only recommended in patients
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with advanced HIV disease. Unfortunately, there is no vaccine available for the
prevention of environmental mycobacterial infections. There are, however, several reports that the vaccine for tuberculosis, Bacille Calmette-Guerin (BCG),
offers some protection against NTM infection in children.
The treatment of environmental mycobacterial infections is almost always
more complicated than the treatment of tuberculosis. The drugs, frequency of
administration, and duration of therapy will vary depending on the species of
NTM causing the disease, site of infection, and extent of disease. Although
some antituberculous drugs are also active against NTM, treatment of most
infections also requires antibiotics that are not typically used to treat tuberculosis. The treatment may depend on laboratory tests of antibiotic resistance of the
isolate causing disease. Prolonged courses of intravenous or inhaled antibiotic
therapy may be required.
The prognosis for pulmonary infections due to environmental mycobacteria
is variable and depends on many factors, including the specific species involved
and its drug susceptibility pattern, extent of disease, presence of other medical
problems, and whether or not the patient can tolerate the treatment regimen. For
example, the cure rate for disease caused by M. kansasii is virtually 100 percent, while that for diseases caused by M. avium is 30 to 85 percent. A cure is
seldom achieved in patients with pulmonary M. abscessus infection (1).
Are we making a difference?
Research past, present, and future
Compared to other lung diseases, relatively little progress has been made in understanding, preventing, or treating disease due to NTM. Although these organisms
can be isolated from the environment, it is not clear when and where exposures
occur and why some people develop infection but most do not. Few clinical trials
have been performed, and most have been small, non-randomized, and uncontrolled. Based on these trials, however, recurrence rates with pulmonary disease
appear to be high. Whether this high recurrence is due to failure of the recommended treatment regimens or re-infection with another strain is not clear.
Information is emerging from basic science research. The nature of the ­different
mycobacterial species, their requirements for growth, and their ­adaptation to different environments are being learned. Individuals with defects in their immune systems are more susceptible to NTM, and the nature of this susceptibility gives
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Leonid Heifets
Nontuberculous Mycobacterial Disease
The different species of mycobacteria can be identified based on several
factors, such as their appearance when grown in laboratory media. The
larger, rough-looking colonies are Mycobacterium chelonae, and the
smaller, smooth colonies are Mycobacterium avium.
insights into the immune responses that control the disease. The ability of mycobacteria to live in biofilm may partly explain how they survive in the mucus of the
airways of patients with bronchiectasis in the presence of ­antibiotics.
What we need to cure or eliminate nontuberculous
mycobacterial infections
The recently documented increase in NTM infections should be a stimulus to
develop better diagnostic tests and discover new drug therapies. Large-scale
randomized clinical trials are needed to discover which drugs are best, how long
patients should be treated, and which combinations will decrease drug-related
toxicity. A better understanding of the transmission and pathogenesis of these
increasingly common infections may allow prevention of harm from these ubiquitous environmental bacteria.
Only some of the extensive research on M. tuberculosis can be applied to the
environmental mycobacteria, but breakthroughs in tuberculosis may be adaptable to other mycobacterial diseases. For example, a blood test similar to the one
used for the diagnosis of tuberculosis could be developed. Medications and vaccines being developed for tuberculosis could be tested in NTM disease. There is
an urgent need, however, to develop tools for these diseases on their own.
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References
1. Griffith DE, Aksamit T, Brown-Elliot BA, Catanzaro A, Daley C, Gordin F, Holland SM,
Horsburgh R, Huitt G, Iademarco MF, et al, for the ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA
statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.
Am J Respir Crit Care Med 2007;175:367–416.
2. Marras TK, Chedore P, Ying AM, Jamieson F. Isolation prevalence of pulmonary non­tuberculous mycobacteria in Ontario, 1997–2003. Thorax 2007;62:661–666.
3. Iseman MD, Marras TK. The importance of nontuberculous mycobacterial lung disease.
Am J Respir Crit Care Med 2008;178:999–1000.
4. Edwards FG. Disease caused by ‘atypical’ (opportunist) mycobacteria: a whole population
review. Tubercle 1970;51:285–295.
5. Khan K, Wang J, Marras TK. Nontuberculous mycobacterial sensitization in the United
States: national trends over three decades. Am J Respir Crit Care Med 2007;176:306–313.
6. Reed C, von Reyn F, Chamblee S, Ellerbrock TV, Johnson JW, Marsh BJ, Johnson LS,
Trenschel RJ, Horsburgh CR Jr. Environmental risk factors for infection with Mycobacterium
avium complex. Am J Epidemiol 2006;164:32–40. 6a. Ballarino GJ, Olivier KN, Claypool RJ,
Holland SM, Prevots DR. Pulmonary nontuberculous mycobacterial infections: antibiotic
treatment and associated costs. Respir Med 2009;103:1448–1455.
7. Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis. Thoracic
anomalies associated with pulmonary disease caused by Mycobacterium avium complex.
Am Rev Respir Dis 1991;144:914–916.
8. Prince DS, Peterson DD, Steiner RM, Gottlieb JE, Scott R, Israel HL, Figueroa WG, Fish JE.
Infection with Mycobacterium avium complex in patients without predisposing conditions.
N Engl J Med 1989;321:863–868.
9. Kim RD, Greenberg DE, Ehrmantraut ME, Guide SV, Ding L, Shea Y, Brown MR, Chernick
M, Steagall WK, Glasgow CG, et al. Pulmonary nontuberculous mycobacterial disease:
prospective study of a distinct preexisting syndrome. Am J Respir Crit Care Med
2008;178:1066–1074.
Web sites of interest
American Thoracic Society
An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous
Mycobacterial Diseases
www.thoracic.org/statements/resources/mtpi/nontuberculous-mycobacterial-diseases.pdf
National Jewish Health
www.nationaljewish.org
NTM Info & Research, Inc.
www.ntminfo.com
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